A method of administering a drug whereby a fine drug powder can be accurately administered to a target site (in particular, a target site in the body cavity) via fluidization and spraying with a gas by using a micro tube. Concerning the administration mode, in particular, the drug alone or a biopolymer is administered or the biopolymer is employed as a carrier in the above method. More specifically speaking, a method of administering a fine drug powder which comprises finely milling one or more types fine particles of the drug and/or the biopolymer, blending them each other, fluidizing the blend with a gas, then transporting the fluidized matter in a micro tube by the gas stream and spraying the fine drug powder from the tip of the micro tube toward the target site. Further, an administration method which comprises concentrically providing a capillary tube in the micro tube, supplying an aqueous solution of the drug and/or the biopolymer from the capillary tube into the gas stream and then mixing it with other fine particles of the drug and/or the biopolymer under transportation by the gas.

Description of the Invention

SUMMARY OF THE INVENTION

In order to solve the problems disclosed in the present application, an aspect of the present invention according to claim 1 is a method for administering a finely powdered drug, characterized in that the drug is pulverized to have a mean particle diameter of equal to or less than 100 .mu.m to provide flowability with a gas, a homogeneous fluid of the fine powder and the gas is prepared and transferred through a micro tube by a flow of the gas, and the finely powdered drug is sprayed on a target site from a tip of the micro tube, the quantity sprayed thereof being adjustable.

Another aspect of the present invention according to claim 2 is a method for administering a biopolymer comprising fluidizing one or more types of fine particles of a biopolymer with a gas to prepare a homogeneous mixed-phase fluid of the biopolymer and the gas; transferring the mixed-phase fluid through a micro tube by flowing the gas; and spraying the fine particles of the biopolymer toward a target site from a tip of the micro tube, thereby providing hemostasis at a wound site, providing a seal thereto, preventing adhesion of an organ and healing a wound.

Specifically, the administration method according to the present invention has a configuration that includes pulverizing the drug and the biopolymer to reduce the unit weight of the pulverized powder, fluidizing thereof with the carrier gas, transferring thereof through the micro tube, and injecting the finely powdered drug and the biopolymer from the tip of the micro tube, and, being so configured, the drug and the biopolymer can be precisely administered through a narrow space from the surface of the body to the target site positioned in a deeper part of the body to which the administration thereof has been conventionally impossible. Various types of biopolymers have been employed for hemostasis, sealing, prevention of the adhesion of an organ, wound healing or the like. The type and the formulation of a plurality of biopolymers for use is different depending on objectives of the medical treatment, and the dosage thereof is also different. However, the method of the present invention, can provide the advantageous effect of precise administration of these biopolymers.

In the administration method according to the present invention, the finely powdered drug can be mixed with the fine particle of the biopolymer as a drug carrier, and administered to the target site by utilizing fluid dynamics of the gas. Therefore, in order to improve an adhesiveness of a drug to a target site, yet other aspect of the present invention according to claim 3 is a method for administering a biopolymer, comprising mixing fine particles of a carrier of a bioabsorbable biopolymer with a finely powdered drug; transferring the powder fluidized with a gas through a micro tube by flowing the gas; and spraying a mixed powder of the biopolymer and the finely powdered drug toward a target site from the tip of the micro tube, thereby providing hemostasis at a wound site, providing a seal thereto, preventing adhesion of an organ and healing a wound.

In the administration method according to the present invention, it was found that vibrating the vessel for mixing the fine particle powder and the gas achieves greater efficiency in the fluidization of the fine particle powder to be administered at a highly reproducible concentration and improves the fluidity thereof with the gas. Therefore, yet other aspect of the present invention according to claim 4 is the method according to any one of claims 1 to 3, wherein a homogeneous fluid of a finely powdered drug and a gas or a homogeneous fluid of a biopolymer and a gas, or a homogeneous fluid of a finely powdered drug and a gas with a biopolymer carrier are prepared by vibrating a mixing vessel for mixing the fine drug powder or the biopolymer and the gas. Vibration can be carried out by, for example, rocking vibration, rotational vibration, ultrasonic vibration or the like.

Further, in the administration method according to the present invention, the spraying of a certain quantity to a target site can be achieved by controlling the concentration of the fluidized powder and the flow rate of the gas for the fine particle powder that is sprayed from the tip of the micro tube. Therefore, yet other aspect of the present invention according to claim 5 is the method according to any one of claims 1 to 3, wherein a quantity of the finely powdered drug or the biopolymer sprayed from the tip of the micro tube is adjusted by adjusting the powder concentration of the fluidized powder and the gas flow.

In the administration method according to the present invention, when the drug or the biopolymer for administration is in a solution form, the solution can be injected into the micro tube through a capillary tube having smaller diameter and disposed within the micro tube, so that the size of the liquid droplets of the solution is reduced by being repeatedly adhered onto and separated from the inner wall of the micro tube by the gas flow, and the droplet is sprayed from the tip of the micro tube, thereby enabling the precise administration to the target site. Therefore, yet other aspect of the present invention according to claim 6 is a method according to any one of claims 1 to 5, wherein a small diameter-tube having a smaller diameter than the micro tube is further provided coaxially in the micro tube, and wherein an aqueous solution of physiological saline, an infusion solution or a drug and/or a biopolymer is injected from the smaller diameter-tube into a gas flow in the smaller diameter-tube, thereby spraying a mixture thereof with the drug in the fluidizing gas and/or the biopolymer fine particles in the micro tube.

On the other hand, in contrast to the above-described approach, a tube having a smaller diameter is coaxially provided in the micro tube, and the fine powder fluidized with the gas is transferred through the smaller diameter tube, and an aqueous solution of the drug, biopolymer or the like is transferred through the clearance between the outer tube (the micro tube) and the inner tube (the smaller diameter tube), and the respective aqueous solutions are mixed at a position in the vicinity of the outlet of the micro tube and sprayed, thereby enabling precise administration to the target site. Therefore, yet other aspect of the present invention according to claim 7 is a method according to any one of claims 1 to 5, wherein a smaller diameter-tube having a smaller diameter than the micro tube is further provided coaxially in the micro tube, wherein the finely powdered drug is transferred by the gas flow through the smaller diameter-tube and an aqueous solution of a physiological saline, an infusion solution or a drug and/or a biopolymer is transferred through the clearance between the inner and the outer tubes, and wherein both of the finely powdered drug and the aqueous solution to be sprayed is mixed at the tip of the micro tube.

Further, yet other aspect of the present invention according to claim 8 is a method according to any one of claims 1 to 7, wherein the drug fluidized with the gas is provided with sustained release, thereby delaying the release of the medicinal properties, and another aspect of the present invention according to claim 9 is a method according to claim 8, wherein the release of the medicinal properties is delayed by microencapsulating, spray drying or freeze drying of the drug.

In addition, a further aspect of the present invention according to claim 10 is a method for administering a drug comprising fluidizing a biopolymer fine powder and fluidizing of a finely powdered drug in different vessels, transferring the respective fine powders by gas flow through a micro tube, spraying the fine powders from a tip of the micro tube to a target site by first spraying the finely powdered drug and second spraying the fine particles of the biopolymer to coat the drug component layer on the target site, thereby preventing diffusion and leakage of the drug to a location other than the target site.

Specifically, according to the present invention, the drug fine powder is sprayed and applied onto the target site by utilizing the fluid dynamics of the gas, and the drug adhesion surface is then further coated with the fine particle of the biopolymer, thereby ensuring leakage and diffusion of the drug fine powder to a portion other than the target site is prevented.

Further, yet other aspect of the present invention according to claim 11 is a method for administering a drug comprising connecting containers containing two types of respectively different components in series with a micro tube and spraying a drug from a tip of the micro tube to a target site, wherein a larger quantity of the component contained in the vessel that is connected nearer to the tip of the micro tube is sprayed than that contained in the other vessel in the first half of the spraying, and wherein a larger quantity of the component contained in the vessel that is connected at the gas input portion side is sprayed than that contained in another vessel in the second half of the spraying, thereby gradually varying the concentrations of the respectively sprayed components.

Specifically, according to the method of the present invention, the coating layer covering the administered site by the spraying can be formed to have a concentration distribution of the components that has an automatically-formed gradient from the interior side of the administered site to the exterior side thereof. For example, an inner layer in vicinity of an injured surface can be coated with a composition containing a component promoting the healing of the injury at a higher concentration, and the outer layer can be coated with a biopolymer having better sealing properties. Such spray coatings, for example, can be achieved by a method in which two vessels containing fine powder gases or two vessels containing aqueous solutions are coupled in series, and the component from the vessel further from the spray slot is transfered to the nearer vessel, and the two components are gradually mixed to provide a concentration gradient.

Alternatively, in the present invention, a plurality of biopolymer, in particular two types of biopolymers that are water-soluble, exhibiting a viscous nature or be coagulated, can be administered, and in such case, a set of fine particle powder thereof and solution thereof, or a set of solutions thereof can be administered to the target site. Therefore, yet other aspect of the present invention according to claim 12 is a method for administering a biopolymer, wherein two types of biopolymer, which can be dissolved in water to exhibit a viscous nature or be coagulated, are employed, and wherein a set of fine particle powder thereof and solution thereof, or a set of solutions thereof are individually transferred through respective micro tubes by flows of gases, and the set are mixed at a tip of the micro tube, thereby spraying thereof to a target site.

In this case, if the two types of the biopolymer is a set of an anionic biopolymer and a cationic biopolymer, both in a solution state can be combined to exhibit physical properties and bio-combinability that are totally different from those of the single component thereof, and in particular, the increase of viscosity is remarkable. Although the combined compound of the both biopolymers is difficult to be transported through the micro tube due to its high viscosity, the highly viscous gel compound having greater adhesiveness can be sprayed to the target site by transporting one of the biopolymers as a form of fine particle powder with a gas flow or transporting both biopolymers as a form of solution with a gas flow, and mixing thereof when spraying.

Therefore, yet other aspect of the present invention according to claim 13 is the method for administrating a biopolymer according to claim 12, wherein the set of the two types of biopolymers is a combination of an anionic biopolymer and a cationic biopolymer, and yet other aspect of the present invention according to claim 14 is the method for administering a biopolymer according to claims 12 or 13, wherein the biopolymers are selected from a group consisting of synthetic polymers, polysaccharides, peptides and proteins.

More specific aspect of the present invention according to claim 15 is a method for administering a drug for providing a hemostasis of a wounded face or providing a seal, characterized in that two capillary tubes are coaxially provided within a micro tube, and fibrinogen alone or a combined liquid thereof with other coagulation factor and thrombin alone or a combined solution thereof with calcium chloride are injected from one capillary tube and another capillary tube, respectively, into a gas flow in the micro tube, thereby spraying the mixture from a tip of the micro tube to a target site while mixing both solutions.

In such case, further specific aspect of the present invention according to claim 16 is a method for administering a drug for providing a hemostasis of a wounded face or providing a seal, characterized in that a powder containing fibrinogen as a chief constituent alone or a mixed fine powder thereof with a biopolymer and an aqueous solution containing thrombin as a chief constituent are employed, and a mixture thereof are sprayed to a target site.

The powder containing fibrinogen as a main constituent can be a powder containing, for example, fibrin, coagulation factor XIII, fibronectin, aprotinin or the like, and a powder containing thrombin as a chief constituent can be a combined powder of thrombin and calcium chloride.

Further, yet other aspect of the present invention according to claim 17 is a fluidized matrix fine particle powder for use as a drug having sustained releaseability in the methods for administering the drug according to any one of claims 1 to 16, wherein the drug is bound to a biopolymer within a solution via an intermolecular interaction consisting of a coulomb force, a hydrogen bonding and a hydrophobic bonding and pulverized at a lower temperature after drying. In this case, properties of the matrix can be utilized to ensure the sustained release of the drug.

Here, when the biopolymers having different ion charges are mixed, the mixture acquires new physical properties due to containing ionic bonds therein, and the increase of viscosity or the reduction of solubility is remarkable. Therefore, a powder prepared by mixing, formulation-processing or chemically combining one electric charged polymer with a drug having an opposite electric charge is fluidized with gas and is mixed and injected with a biopolymer solution having an opposite electric charge to form a sparingly soluble and sparingly degradable gel or semisolid material, thereby enabling to provide a sustained release to the drug administration target site and coating thereof. Further, the physical properties thereof comprise functional characteristics as a drug for hemostasis, prevention of adhesion wound healing and tissue sealing.

Therefore, yet other aspect of the present invention according to claim 18 is a method for administering a drug for providing a hemostasis of a wounded face or providing a seal, wherein the drug according to claim 17 and a biopolymer having an ionic charge opposite to that of the matrix fine particle powder of the biopolymer according to claim 17 are sprayed to a target site from a tip of a micro tube in a fine particle powder state or a solution state.

In addition, the administration method according to the present invention enables spray-administering of an adhesive and filler employed for treatments of bone in orthopedic surgery. Since the adhesive and the filler employed for treatments of bone in orthopedic surgery are generally administered by mixing the ceramics powder and the liquid binder with a spatula and rubbing the mixture on target site, the internal load is generated therein and uniform surface is seldom formed. However, since the ceramics powder is administered via fluidization and spray-administration according to the administration method of the present invention, the ceramics powder can be precisely administered to a larger defective part of a skull and a defective part of the bone that is caused in a surgical removal operation of cancer, which requires a delicate handling, and thus, forming of the bone substitute can easily be conducted, even if the operation field is narrow.

Therefore, yet other aspect of the present invention according to claim 19 is the method according to any one of claims 2 to 7, wherein the biopolymer is a calcium phosphate-type powder, a hydroxyapatite-type powder or a powder of a glass-type material, which is a bone cement or an artificial bone filler, and wherein a mixed solution of a calcium phosphate-type powder or a hydroxyapatite-type powder and a liquid binder agent, or a mixed solution of glass-type material and an aqueous acids is sprayed from a tip of a micro tube to form a bone substitute at a target site.

BEST MODE FOR IMPLEMENTING THE INVENTION

The biopolymer used in the present invention is, in one sense, a polymer having so-called biocompatibility, and as a typical biopolymer is not particularly limited as long as the polymer has functions for hemostasis, prevention of adhesion, prevention of keloid, healing of wounds, closing of wounds, sealing and the like. More specifically, carboxymethyl celluloses, carboxyethyl celluloses, oxycelluloses, agaroses, chitins, chitosans, hyaluronic acids, starches, glycogens, alginates, pectins, dextrans, chondroitin sulfates, gelatins, collagens or the like can be employed, or one or more types of these biopolymers can be employed.

Further, the compound having bioabsorbability can be employed as the biopolymer, and such bioabsorbable materials can be polylactic acids, lactic acid-ethylene glycol copolymers, collagens, agaroses, polyvinyl alcohols, fibrin gels, gelatins, chitins, chitosans, oxycelluloses, carboxymethyl celluloses, pectins, starches, dextrans, agaroses, alginic acids, chondroitins, chondroitin sulfates, fucoses, carrageenans, ethylene-vinyl acetate copolymers, polyglycolic acids, lactic acid-caprolactone copolymers, calcium phosphates, calcium carbonates, hydroxyapatites or the like.

Further, the drugs capable of being administered with the present invention can include various types of drugs, and among these, typical drugs can be drug medicines possessing lower molecular weights, such as bactericides, antibiotic agents, hemostats, anti-tumor drugs and antiphlogistics, peptides such as cell growth factors, cytostatic factors, neurotrophic factors or the like, protein medicines or various types of antibody medicines, vectors containing genes utilized for gene therapy (adenovirus, retrovirus, liposome, hydrogel or the like) or naked DNA or the like.

These drugs can be administered as fine powders or aqueous solutions by the administration method according to the present invention. Among these, in the case that the drug is administered as fine powder with the biopolymer, when the isoelectric point with the biopolymer is dissociated, the adhesion of the drug can be improved and the release ability of the drug from the biopolymer can be decreased by containing ion-bonds or the like therein, thereby providing better sustained release. Therefore, the method also has the advantages of being capable of appropriately selecting the type of biopolymer depending on the type of the drug for administration.

In order to ensure the sustained release of the drug for usage, the powder prepared by the method, in which the drug having an electric charge is previously ion-bonded to a biopolymer having different electric charge in an aqueous solution, then freeze-dried and thereafter pulverized to be unified, can be administered by the administration method of the present invention.

As an alternative approach for providing sustained release, the drug for administration is microencapsulated to form fine particles, and these fine particles, either alone or with a biopolymer, can be administered by the administration method of the present invention.

In the administration method of the present invention, the drug and/or the biopolymer is precisely administered to the target site basically by fluidizing the drug and/or the biopolymer in the carrier gas flow, transferring thereof through the micro tube, and injecting the fine particles of the drug and/or the biopolymer from the tip of the micro tube. Therefore, it is preferable to employ fine particles, which are capable of being fluidized by the drug and/or the carrier gas. Such fine particles can preferably have a particle size distribution, in which roughly 80% particles have particle diameters under 100 .mu.m, and the mean particle diameter is equal to or less than 50 .mu.m.

Here, in the administration method of the present invention, the administered drug and/or biopolymer are not particularly limited to the form of the fine particles, and it is needless to say that even a solution-type thereof can be administered according to the administration method of the present invention.

Although various types of gases are included in the carrier gases available for the present invention, it is preferable to employ carbon dioxide gas or nitrogen gas in view of safety and convenience. It is preferable to use gas-piping facilities in a hospital for the injection gas.

A fluidization of the drug and/or the biopolymer in the administration method of the present invention can preferably be conducted within a blending cell for the gas and the pulverized powder. Further, in order to mix a liquid and the fine powder, which is fluidized with gas, the liquid can be injected into a micro tube via a capillary tube, where the liquid and the powder come into contact and can be mixed. The flow rate of the gas flowing through the micro tube can be at a level that promotes fluidizing a sufficient amount of the gas for spraying the mixture of the drug from the tip of the micro tube, and after setting such a flow rate for the gas, for example, bacteria or the like are removed via passage through a bacteria filter, the powder is fluidized within a powder blending cell, further the fine particles of the drug and/or the biopolymer are transferred through the micro tube, the drug and the like is sprayed from the tip of the micro tube, thereby being sprayed to the targeted administering site, in particular the administration site in a living body.

The administration method of the present invention will be described in detail as follows, with reference to FIG. 1 (see Original Patent) that shows a schematic diagram thereof.

The FIG. 1 (see Original Patent) schematically shows a fundamental configuration for the administration method of the present invention. Specifically, a fluidizing gas such as carbon dioxide gas or nitrogen gas flows from a gas supply source (A) of an outside facility (101), and after the pressure thereof is adjusted via a pressure regulating valve (B), the flow is modulated by a gas flow rate control valve (D) and a flow meter (C) on the apparatus portion (102), and then, the bacteria included in the gas are removed by a bacteria filter (F), and thereafter, the flow is eventually supplied to a powder-gas mixing cell (E), where the drug and/or the biopolymer are fluidized.

The fluidization of the drug and/or the biopolymer in the blending cell can preferably be conducted within the blending cell that is a quantification mixer comprising a rolling shaker, a rotary shaker or a supersonic wave shaker, and the powder of the drug and/or the biopolymer is uniformly mixed and fluidized by the gas in the interior of the quantification mixer (blending cell). The mixed powder fluidized by the gas is then transferred through the micro tube (103) by the gas to be sprayed from the tip of the micro tube (103). In this case, the bacteria filter-blending cell-micro tube portion of the apparatus portion (102) can be a disposable portion (104), which is easily replaced depending upon the type of the drug and/or the biopolymer suitable for the administration target.

When the drug and/or biopolymer to be administered by the administration method described above is in a solution form, a capillary tube (104) is provided coaxially within the micro tube (103), and when the liquid-type drug and/or biopolymer is injected from the tip of the capillary tube toward the gas flow in the micro tube (shown by an arrow in the figure), the liquid is dispersed by the gas flow to form a mist, and then the mist is sprayed from the tip of the micro tube, thereby enabling the spraying thereof onto the target site. A schematic structure of the micro tube, which can be used for in this case, is shown in FIG. 2 (see Original Patent).

Alternatively, two or more types of the liquids of the drug and/or the biopolymer can be mixed for administering via the administration method of the present invention. In such case, two or more of the capillary tubes (105,106) are installed coaxially within the micro tube (103) as required, and the individual solutions of the drug and/or the biopolymer are injected into the gas flow in the micro tube (shown by an arrow in the figure) from the tip of the capillary tube to form a mist, and the mist can be sprayed from the tip of the micro tube. The schematic structure of the micro tube is shown in FIG. 3 (see Original Patent).

Alternatively, a modification of the administration method of the present invention can employ a small cylinder as the supply source of the fluid gas. Further, if a micro tube is coupled to an aerosol, and a capillary tube is combined with the micro tube, achieving a miniaturization thereof or providing a disposable application is possible. In this case, two types of aerosols are combined and coupled via a nozzle, and two types of drug and/or biopolymer are simultaneously injected from the respective aerosols and mixed in the coupled portion, and then the drug and/or the biopolymer can be sprayed from a tip of an integrated micro tube.
 

Claim 1 of 10 Claims

1. A method for administering a biopolymer having hemostatic or adhesion preventing functions, comprising the steps of: fluidizing fine particles of the biopolymer having hemostatic or adhesion preventing functions with a gas to prepare a homogenous mixed-phase fluid; transferring the mixed-phase fluid through at least one micro-tube by flowing the gas; mixing a liquid with the mixed-phase fluid, the liquid being selected from the group consisting of a saline solution, an infusion solution, an aqueous solution of a drug and an aqueous solution of a biopolymer; the liquid being injected into the micro-tube thorough at least one inner tube so that the liquid is mixed with the mixed-phase fluid, wherein the inner tube is configured to be within the micro-tube; spraying the mixed liquid and the mixed-phase fluid toward a target site from an open tip of the micro-tube; wherein the mixed liquid and the mixed-phase fluid become a gel compound after the liquid and the mixed-phase fluid are mixed; whereby the fine particles of the biopolymer are capable of being sprayed as a gel compound toward the targct site to provide a seal upon the target site.
 

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